CN103626772A

CN103626772A - Synthetic method for temozolomide and intermediate

Info

Publication number: CN103626772A
Application number: CN201210303798.8A
Authority: CN
Inventors: 不公告发明人
Original assignee: Sinopharm Yixin Pharmaceutical Co Ltd
Current assignee: Sinopharm Yixin Pharmaceutical Co Ltd
Priority date: 2012-08-24
Filing date: 2012-08-24
Publication date: 2014-03-12
Anticipated expiration: 2032-08-24
Also published as: CN103626772B

Abstract

The invention discloses a modified optimized synthetic method for temozolomide and an intermediate thereof. The synthetic method is characterized in that a new oxidation ring-closing reagent is introduced for a reaction with lithium chloride and sodium nitrite in an aqueous solution, and the synthetic method helps to improve the yield of the reaction, increase the controllability on the reaction and avoid usage of methyl isocyanate with relatively high toxicity.

Description

The synthetic method of a kind of Temozolomide and intermediate

Technical field

The present invention relates to a kind of high efficiency synthetic method of antitumor drug Temozolomide.

Background technology

Temozolomide, chemistry 3-methyl-8-aminocarboxyl-imidazo [5,1-d]-1,2,3 by name, 5-4 (3H)-one, is a kind of newtype drug that cerebral glioma is had to good therapeutic effect; There is bioavailability high, can be oral, be easy to see through hemato encephalic barrier, than the toxicity that do not superpose, there is wider antitumor spectrum with other drug.At present, Temozolomide is the cancer therapy drug for the treatment of preferably cerebral glioma and malignant melanoma.

The conventional synthetic method of Temozolomide is to be that raw material reacts with Sodium Nitrite from 5-amino-1H-imidazoles-4-methane amide or its hydrochloride, through diazotization, react and make Temozolomide (referring to J. Med. Chem. with methyl isocyanate (MIC) again, 1984,27,196-201 and Chem. Commun., 1994,1687-1688).But because MIC toxicity is large and reaction conditions is difficult to control, be difficult for transportation, to production, brought certain difficulty.In WO2008038031, adopt lithium chloride, Sodium Nitrite cyclization, avoided the use of toxic agent methyl isocyanate, but reaction yield is still not high.The present invention introduces new oxidation cyclization reagent and reacts in the aqueous solution with lithium chloride, Sodium Nitrite, improved the productive rate of reaction, increased the controllability of reaction, thereby avoided use methyl isocyanate (MIC) to improve again yield and the purity of end product, reached the object of applicable large-scale industrial production.

Summary of the invention

The object of this invention is to provide that a kind of environmental protection, yield are high, purification process is simply convenient to industrial Temozolomide synthetic method.

The preferred embodiment of the inventive method is to be shown in following scheme, and the common form of this scheme is described in thereafter, scheme I:

In the first step of the method, 5-aminoimidazole-4-carbozamide and p-nitrophenyl chloro-formic ester, at 0 ℃, add triethylamine, take methylene dichloride as solvent reacts, and obtains intermediate 2; In post-processing stages, adopt methylene dichloride and water mixed liquid (methylene dichloride: water=5:1) making beating mode of washing carries out the yield that aftertreatment not only can guarantee reaction, also can obtain the intermediate 2. that purity is higher

Scheme II:

Figure 2012103037988100002DEST_PATH_IMAGE002

This reaction under organic aprotic solvent exists, at ambient temperature or lower than under envrionment temperature for example envrionment temperature be 0 ℃, preferred ambient temperature is 0 ℃ reacts below, the reaction times is 18 hours.The preferred methylene dichloride of described organic aprotic solvent is organic solvent.Yet other organic solvent comprises THF, acetonitrile, ethyl acetate and normal hexane.

Scheme III:

Figure 2012103037988100002DEST_PATH_IMAGE003

In shown in scheme III, the second step of the method, under described reaction normal temperature at inert organic solvents as THF, DMF, DMA and methylene dichloride or wherein carry out in both mixed solvent.Preferably, at 25 ℃ of described reactions, use THF solvent to carry out.Experiment showed, alcohols energy and intermediate 2react, thereby affect reaction yield.At J.Org.Chem.1997, in 62,7288-7294., described the synthetic method of this compound, but do not mentioned the concrete post-treating method of this reaction.Post-treating method to this reaction in the present invention have been described in detail.

In the present invention, adopt aqueous methylamine solution to replace J.Org.Chem.1997 as ammonification reagent, the methylamine alcohol solution using described in 62,7288-7294. is as the ammonification reagent of this reaction, thereby improved largely the yield of this step reaction.(filter cake washing with acetone, dries to obtain product for ether: acetone=3:2), making beating is washed 1 hour, suction filtration to adopt ether and acetone mixed solution.The method is simple to operate, and gained intermediate product purity is high, has reached in raw materials medicine the requirement as internal control intermediate.

Scheme IV:

Figure 2012103037988100002DEST_PATH_IMAGE004

The preparation of Temozolomide is shown in scheme IV, the synthetic intermediate that passed through of Temozolomide 3diazotization or carry out corresponding amino oxidation and close ring and form.In this reactions steps, the new oxidative cyclization reagent of introducing, the ring structure that is conducive to reaction carries out, and makes ring-closure reaction more abundant, thereby increases the productive rate of reaction, better meets industrial prospect.

Oxidation cyclization reagent can be I ₂, ICl, ICl ₃and H ₅iO ₆.Preferably dioxide giving reagent is KI.In the method, in inert organic solvents, carry out, inert organic solvents more options non-protonic solvent is DMF, THF, dioxane, acetonitrile, methylene dichloride, toluene for example.Preferably, described organic solvent is methylene dichloride.Carrying out under 0 ℃ of-25 ℃ of proper temperature of described reaction.Preferably, temperature is at 0 ℃.

The invention has the advantages that:

(1) intermediate in scheme III 3synthetic employing aqueous methylamine solution as ammonification reagent, thereby improve largely the yield of this step reaction.

(2) in the synthetic end product Temozolomide process of scheme IV, the oxidation cyclization reagent by new introducing, has shortened the ring-closure reaction time, greatly improved the productive rate of ring-closure reaction, the related marketable material cost of the method is low, and simple to operate in reaction process, stable reaction is easy to control.

(3) whole technique has been avoided using the larger methyl isocyanate (MIC) of toxicity, and this operational path is simple, and productive rate is high, aftertreatment and easily refining, and end product purity is higher, reaches 99.822%, better meets industrial requirement.

accompanying drawing explanation

Fig. 1 is patent route map; Fig. 2 is Temozolomide intermediate nucleus magnetic hydrogen spectrum spectrogram; Fig. 3 is Temozolomide HPLC spectrogram.

Embodiment

Following examples are used for illustrating the present invention, but do not limit in any form the present invention.

The preparation of embodiment 1 Temozolomide

The preparation of steps A intermediate 2

Figure 2012103037988100002DEST_PATH_IMAGE005

To being equipped with in tri-mouthfuls of round-bottomed flasks of 5 L of thermometer, add successively 5-aminoimidazole-4-carbozamide a(80g, 634.32 mmol), methylene dichloride (1920 mL), triethylamine (176.82 mL, 1268.63 mmol)), at 25 ℃, stir 10 minutes, the temperature of reaction system is down to below 0 ℃, after 10 minutes, drip and be dissolved in the 4-chloroformate nitrophenyl ester (255.71 g, 1268.36 mmol) in 1280 mL methylene dichloride, below 0 ℃, react after 4 hours, temperature control, at 25 ℃, reacts 18 hours.By reaction solution Büchner funnel suction filtration, 1000 mL methylene dichloride and 200ml water mixed liquid making beating washing 1 hour for the filter cake obtaining, suction filtration again, filter cake washed with dichloromethane, dries under normal temperature, obtains yellow solid product.Productive rate: 92%, fusing point: 200 ℃ of decomposition.

¹H?NMR(400?MHz?,?DMSO，δppm):?6.54?(brs,?2?H),?6.98?(brs,?1?H),?7.10?(brs,?1?H),?7.75?(d,? J?=?9.22Hz,?2?H),?7.85?(s,?1?H),?8.39?(d,? J=?9.22?Hz,?2?H);

The preparation of step B intermediate 3

In 50 ml round-bottomed flasks, add successively intermediate 2(30g, 103.02 mmol), solvents tetrahydrofurane 240 ml, stirred after 10 minutes, added slowly 33% methylamine alcohol solution (12.6 mL, 103.02 mmol), and temperature is controlled at 25 ℃, reacts 5 hours.By reaction solution Büchner funnel suction filtration, and the filter cake obtaining use 300mL ether and the washing of 200ml acetone mixed solution (ether: acetone=3:2), stirring to pulp 1 hour, suction filtration filter cake washing with acetone, dry to obtain light yellow product, productive rate: 87%, fusing point: 170 ℃ (decomposition).

¹HNMR(400MHz?,?DMSO，δppm):?8.46?(1?H,?q,?NH),?7.62?(1?H,?s,?CH),?6.83?(1?H,?bs,?NH),?6.39?(2?H,?brs,?NH ₂),?2.78?(3?H,?d,?CH ₃).

The preparation of step C Temozolomide

Figure 2012103037988100002DEST_PATH_IMAGE007

Get tri-mouthfuls of round-bottomed flasks of 1L, add successively in order a hydration lithium chloride (373.03g, 6175 mmol), Glacial acetic acid (29mL), and water (290ml).At normal temperatures, stir 30 minutes.Add intermediate 3(29g, 158.32 mmol), at normal temperatures, stir after 30 minutes, reaction flask is placed in to coolant circulation pump, control temperature below 0 ℃, after cooling 10 minutes, the aqueous solution (14.5 g are dissolved in 58 ml water) that drips Sodium Nitrite, is controlled at temperature in-10 ~ 5 ℃, by reaction mixture in 0 ~ 5 ℃, stir after one hour, add I ₂(4.00g, 15.8mmol), then reacts after 2 hours at normal temperatures, by the aqueous solution of Sulfothiorine (29 g are dissolved in 290 ml water), stirs after 20 minutes, finishes reaction.Uses 5L dichloromethane extraction at every turn, extract 8 ~ 10 times, and after extraction liquid is filtered, concentrated by rotary evaporation reclaims solution, be concentrated into solvent 100 ml left and right, after carrying out suction filtration, obtain pink colour Temozolomide finished product, fusing point: 212 ℃ (decomposition).

¹HNMR(400?MHz?,?DMSO),?δ:?8.80?(s,?1H),?7.80?(brs,?1H),?7.66?(brs,?1H),?3.43(s,?3H);

Temozolomide finished product is refining by the thick product of Temozolomide with acetone soln at normal temperatures, and the washing of pulling an oar, washs 2 ~ 3 times, and suction filtration obtains product, productive rate: 76%, through liquid phase analysis purity 99.82%.

Claims

1. a synthetic method for Temozolomide and intermediate, comprises the following steps:

A. 5-aminoimidazole-4-carbozamide-1H-formic acid p-nitrophenyl ester is synthetic: 5-aminoimidazole-4-carbozamide and p-nitrophenyl chloro-formic ester, at 0 ℃, add triethylamine, the methylene dichloride of take reacts as solvent, obtain 5-aminoimidazole-4-carbozamide-1H-formic acid p-nitrophenyl ester in post-processing stages, adopted methylene dichloride and water mixed liquid (methylene dichloride: water=5:1), making beating mode of washing.

B. 5-aminoimidazole-4-carbozamide-1-n-formyl sarcolysine acid amides is synthetic: add 5-aminoimidazole-4-carbozamide-1H-formic acid p-nitrophenyl ester, solvents tetrahydrofurane, stir after 10 minutes, add slowly aqueous methylamine solution, temperature is controlled at 25 ℃, react 5 hours. by reaction solution Büchner funnel suction filtration, ether and the washing of acetone mixed solution for the filter cake obtaining, making beating washing 1 hour, suction filtration, filter cake washing with acetone, dries to obtain light yellow product.

C. Temozolomide is synthetic: by Lvization Li ﹑ Glacial acetic acid, and water, at normal temperatures, stir 30 minutes. add 5-aminoimidazole-4-carbozamide-1-n-formyl sarcolysine acid amides, at normal temperatures, stir after 30 minutes, control temperature below 0 ℃, after cooling 10 minutes, drip the aqueous solution of Sodium Nitrite, in titration, temperature is controlled in-10 ~ 10 ℃, by reaction mixture in 0 ~ 5 ℃, stir after one hour, add KI, then react at normal temperatures complete, by the aqueous solution of Sulfothiorine, stir after 20 minutes, finish reaction. with dichloromethane extraction, and by extraction liquid with concentrated after filtration drying, suction filtration obtains the thick product of Temozolomide.

D. Temozolomide is refining: with acetone soln at normal temperatures, carry out abundant agitator treating, suction filtration obtains product.

2. method described in claims 1, wherein the ratio of the methylene dichloride described in step a and water is 5:1, making beating washing.

3. method described in claims 1, wherein the ratio of the ether described in step b and acetone is 3:2.

4. method described in claims 1, wherein adds KI described in step c, and the reaction times is 2 hours at normal temperatures.

5. method described in claims 1, wherein the KI:LiCl ratio that adds described in step c is 3:1 ~ 8:1(mol ratio).

6. method described in claims 1, is wherein preferably controlled at temperature in-10 ~ 5 ℃ in titration in step c.

7. method described in claims 1, wherein washs at 10 ~ 40 ℃ with acetone soln in steps d.